This is a U.S. National Stage filing under 35 U.S.C. 371 of International Patent Application No. PCT/GB98/03496, filed Nov. 24, 1998, which is based on British Patent Application No. 9725244.9, filed Nov. 29, 1997.
The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing an oxazolidinone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded primarily as effective against Gram-positive pathogens because of their particularly good activity against such pathogens.
Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus (MRSA), methicillin resistant coaguiase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium. 
The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens.
The present inventors have discovered a class of antibiotic compounds containing an oxazolidinone ring which has useful activity against Gram-positive pathogens including MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both aminoglycosides and clinically used xcex2-lactams.
We have now discovered a range of compounds which have good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics. In comparison with compounds described in the art (Walter A. Gregory et al in J.Med.Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al in J.Med.Chem. 1992, 35, 1156-1165) the compounds also possess a favourable toxicological profile.
Accordingly the present invention provides a compound of the formula (I): 
wherein R1 is hydroxy, amino, chloro, fluoro, (1-4C)alkanesulfonyloxy, azido, (1-4C)alkoxy, or of the formula xe2x80x94NHC(xe2x95x90O)Ra wherein Ra is hydrogen, (1-4C)alkoxy, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl or (1-4C)alkyl;
R2 and R3 are independently hydrogen or fluoro;
R5 and R6 are independently selected from hydrogen, (1-4C)alkyl, halo and trifluoromethyl;
R4 is xe2x80x94Xxe2x80x94Yxe2x80x94Het.;
wherein X is a direct bond or xe2x80x94CH(OH)xe2x80x94 and
Y is xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(CH2)mxe2x80x94, xe2x80x94COxe2x80x94(CH2)mxe2x80x94, xe2x80x94CONHxe2x80x94(CH2)mxe2x80x94, xe2x80x94C(xe2x95x90S)NHxe2x80x94(CH2)mxe2x80x94 or xe2x80x94C(xe2x95x90O)Oxe2x80x94(CH2)mxe2x80x94;
or wherein X is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94CH(Me)xe2x80x94(CH2)mxe2x80x94 and Y is xe2x80x94(CH2)mxe2x80x94NHxe2x80x94(CH2)mxe2x80x94, xe2x80x94COxe2x80x94(CH2)mxe2x80x94, xe2x80x94CONHxe2x80x94(CH2)mxe2x80x94, C(xe2x95x90S)NHxe2x80x94(CH2)mxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94(CH2)mxe2x80x94 or xe2x80x94S(O)pxe2x80x94(CH2)mxe2x80x94;
or wherein X is xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2NHxe2x80x94 or xe2x80x94CH2N(R)xe2x80x94 [wherein R is (1-4C)alkyl] and Y is xe2x80x94COxe2x80x94(CH2)mxe2x80x94, xe2x80x94CONHxe2x80x94(CH2)mxe2x80x94 or xe2x80x94C(xe2x95x90S)NHxe2x80x94(CH2)mxe2x80x94; and additionally Y is xe2x80x94SO2xe2x80x94 when X is xe2x80x94CH2NHxe2x80x94 or xe2x80x94CH2N(R)xe2x80x94 [wherein R (1-4C)alkyl], and Y is xe2x80x94(CH2)mxe2x80x94 when X is xe2x80x94CH2Oxe2x80x94 or xe2x80x94CH2N(R)xe2x80x94;
wherein n is 1, 2 or 3; m is 0, 1, 2 or 3 and p is 0, 1 or 2; and when Y is xe2x80x94(CH2)mxe2x80x94NHxe2x80x94(CH2)mxe2x80x94 each m is independently selected from 0, 1, 2 or 3;
wherein Het. is a heterocyclic ring [which heterocyclic ring may be unsaturated (linked via either a ring carbon or ring nitrogen atom to xe2x80x94Xxe2x80x94Yxe2x80x94) or saturated (linked via a ring nitrogen atom to xe2x80x94Xxe2x80x94Yxe2x80x94), with the proviso that when it is unsaturated and linked via nitrogen to xe2x80x94Xxe2x80x94Yxe2x80x94 the ring is not quaternised] which heterocyclic ring is optionally substituted on an available carbon atom by up to three substituents independently selected from (1-4C)alkyl [optionally substituted by trifluoromethyl, (1-4C)alkyl S(O)pxe2x80x94 (wherein p is 0, 1 or 2), carbamoyl, N-(1-4C)alkyicarbamoyl, di(N-(1-4C)alkyl)carbamoyl, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, cyano, nitro, amino, N-(1-4C)alkylamino, di(N-(1-4C)alkyl)amino or (1-4C)alkanoylamino], halo, trifluoromethyl, (1-4C)alkyl S(O)p(wherein p is 0, 1 or 2), carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, di(N-(1-4C)alkyl)carbamoyl, (2-4C)alkenyl, cyano, nitro, amino, (2-4C)alkanoylamino, (1-4C)alkoxy, di(N-(1-4C)alkyl)aminomethylimino, hydroxy, oxo or thioxo (xe2x95x90S); and optionally substituted on an available nitrogen atom (if the ring will not thereby be quaternised) by (1-4C)alkyl [optionally substituted by trifluoromethyl, (1-4C)alkyl S(O)pxe2x80x94 (wherein p is 0, 1 or 2), (1-4C)alkoxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, di(N-(1-4C)alkyl)carbamoyl, cyano, nitro, amino, N-(1-4C)alkylamino, di(N-(1-4C)alkyl)amino or (1-4C)alkanoylamino] or oxo (to form an N-oxide); and pharmaceutically acceptable salts thereof.
In a further aspect of the invention there is provided a compound of the formula (I) as described hereinabove, wherein when X is a direct bond, Y is additionally xe2x80x94CON(R)xe2x80x94 (CH2)mxe2x80x94 [wherein R is (1-4C)alkyl], and the optional substituents on an available carbon atom in the Het. heterocyclic ring additionally include amino.
The term xe2x80x98alkylxe2x80x99 includes straight chained and branched structures. For example, (1-4C)alkyl includes propyl, isopropyl and t-butyl.
Examples of (1-4C)alkyl include methyl, ethyl, propyl, isopropyl and t-butyl; examples of N-(1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of di(N-(1-4C)alkyl)carbamoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl; examples of (1-4C)alkylS(O)pxe2x80x94 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of (2-4C)alkenyl include allyl and vinyl; examples of (1-4C)alkoxy include methoxy, ethoxy and propoxy; examples of (2-4C)alkanoylamino include acetamido and propionylamino; examples of N-(1-4C)alkylamino include methylamino and ethylamino; example of di-(N-(1-4C)alkyl)amino include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino; examples of (1-4C)alkoxycarbonyl include methoxycarbonyl and ethoxycarbonyl; examples of halo include fluoro, chloro and bromo; examples of di-(N-(1-4C)alkyl)aminomethylimino include dimethylaminomethylimino and diethylaminomethylimino and examples of (1-4C)alkanesulfonyloxy include methylsulfonyloxy and ethylsulfonyloxy.
A heterocyclic ring means a 5- or 6-membered monocyclic ring or a 5/6 or 6/6 bicyclic ring (linked via either, or any, of the rings) containing up to four heteroatoms selected independently from O, S and N. An unsaturated ring means a fully unsaturated (aromatic) ring and partially unsaturated ring systems (such as, for example, tetrahydropyridine). Preferred examples of unsaturated 5- or 6-membered heterocyclic groups with up to four heteroatoms selected independently from O, S and N are furan, pyrrole, thiophene, those containing one, two or three N atoms (for example, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3- and 1,2,4-triazole), two N atoms and one S atom (for example 1,2,4- and 1,3,4-thiadiazole, ), one N and one O atom (for example oxazole, isoxazole and oxazine) and one N and one S atom (for example thiazole and isothiazole). Unsaturated 5-membered heterocyclic groups are preferred. Thiazole is particularly preferred. Links via a ring carbon atom are preferred.
Preferred examples of a 5/6 or 6/6 bicyclic ring (linked via either of the rings) containing up to four heteroatoms selected independently from O, S and N are, for example, indole, quinoline, isoquinoline, benzpyrrole, benzpyrazole, benzimidazole, quinoxaline, benzthiazole, benzoxazole, benzthiadiazole, benztriazole and 1,4-benzodioxan. Preferred are 5/6 bicyclic rings, particularly those containing up to two heteroatoms only, such as benzthiazole and benzoxazole, especially benzthiazole. Links via a ring carbon atom are preferred.
It is to be understood that when a value for xe2x80x94Xxe2x80x94 is a two-atom link and is written, for example., as xe2x80x94CONHxe2x80x94 it is the left hand part (xe2x80x94COxe2x80x94 here) which is bonded to the imidazole ring in formula (I) and the right hand part (xe2x80x94NHxe2x80x94 here) which is bonded to xe2x80x94Yxe2x80x94 in the definition of R4. Similarly, when xe2x80x94Yxe2x80x94 is a two-atom link and is written, for example, as xe2x80x94CONHxe2x80x94 it is the left hand part of xe2x80x94Yxe2x80x94(xe2x80x94COxe2x80x94 here) which is bonded to the right hand part of xe2x80x94Xxe2x80x94, and the right hand part of xe2x80x94Yxe2x80x94(xe2x80x94NHxe2x80x94 here) which is bonded to the Het. moiety in the definition of R4.
Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethyiamine or amino acids for example lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt.
However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
The compounds of the formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I). Examples of pro-drugs include in-vivo hydrolysable (in-vivo cleavable) esters of a compound of the formula (I).
An in-vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include (1-6C)alkoxymethyl esters for example methoxymethyl, (1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and (1-6C)alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in-vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and xcex1-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
The compounds of the present invention have a chiral centre at the C-5 position. The pharmaceutically active enantiomer is of the formula (IA): 
The present invention includes the pure enantiomer depicted above or mixtures of the 5(R) and 5(S) enantiomers, for example a racemic mixture. If a mixture of 5(R) and 5(S) is used, a larger amount (depending up on the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer. Furthermore, some compounds of the formula (I) may have other chiral centres, for example when X is xe2x80x94CH(Me)xe2x80x94.
It will be appreciated that when the Het. moiety in R4 is optionally substituted by hydroxy, oxo or thioxo the phenomenon of tautomerism may be present depending upon the nature of the Het. moiety. Thus, for example, in fully unsaturated (aromatic) systems a hydroxy substituent may represent one tautomeric form, and an oxo substituent the other tautomeric form. The invention includes all tautomeric forms which possess antibacterial activity.
Preferably R1 is of the formula xe2x80x94NHC(xe2x95x90O)Ra wherein Ra is hydrogen, methoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl or (1-4C)alkyl.
Yet more preferably R1 is of the formula xe2x80x94NHC(xe2x95x90O)(1-4C)alkyl.
Most preferably R1 is acetamido.
Preferably one of R2 and R3 is hydrogen and the other is fluoro.
Preferably R5 and R6 are hydrogen.
Preferably the Het. moiety in R4 is unsaturated, ie. fully unsaturated (aromatic) ring or partially unsaturated ring systems. Preferably the Het. moiety in R4 ring is linked via a ring carbon atom.
Preferred values for the Het. moiety in R4 are furan, thiophene, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3- and 1,2,4-triazole, 1,2,4- and 1,3,4-thiadiazole, oxazole, isoxazole, thiazole, isothiazole, indole, quinoline, isoquinoline, benzpyrazole, benzimidazole, quinoxaline, benzthiazole, benzoxazole, benzthiadiazole, benztriazole and 1,4-benzodioxan.
Preferred values for xe2x80x94Xxe2x80x94Yxe2x80x94 links are xe2x80x94CH2Sxe2x80x94, xe2x80x94CH2Oxe2x80x94COxe2x80x94, xe2x80x94CH2NHxe2x80x94, xe2x80x94CH2NHCOxe2x80x94 and xe2x80x94CONHxe2x80x94.
Other preferred values for xe2x80x94Xxe2x80x94Yxe2x80x94 links are a direct link, xe2x80x94CH2SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2NHSO2xe2x80x94, xe2x80x94CH2Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CONHxe2x80x94CH2xe2x80x94, xe2x80x94CONHxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94 and xe2x80x94CON(Me)xe2x80x94.
Preferred optional substituents (preferably, zero, one or two) on an available carbon atom of the Het. moiety of R4 are (1-4C)alkyl, halo, cyano, nitro. amino, (2-4C)alkanoylamino, (1-4C)alkoxy, hydroxy, oxo and thioxo (xe2x95x90S).
Preferred optional substituents (preferably, zero or one) on an available nitrogen atom of the Het. moiety of R4 are (1-4C)alkyl, especially methyl, and oxo (to form an N-oxide).
Accordingly, in a particular aspect of the present invention there is provided a compound of the formula (I) in which R1 is acetamido; one of R2 and R3 is hydrogen and the other is fluoro; R5 and R6are hydrogen; the xe2x80x94Xxe2x80x94Yxe2x80x94 link is xe2x80x94CH2Sxe2x80x94, xe2x80x94CH2Oxe2x80x94COxe2x80x94, xe2x80x94CH2NHxe2x80x94, xe2x80x94CH2NHCOxe2x80x94 or xe2x80x94CONHxe2x80x94; the Het. moiety in R4 is a fully unsaturated (aromatic) ring linked via a ring carbon atom and selected from furan, thiophene, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3- and 1,2,4-triazole, 1,2,4- and 1,3,4-thiadiazole, oxazole, isoxazole, thiazole, isothiazole, indole, quinoline, isoquinoline, benzpyrazole, benzimidazole, quinoxaline, benzthiazole, benzoxazole, benzthiadiazole, benztriazole and 1,4-benzodioxan; wherein the Het moiety is optionally substituted by up to two substituents on an available carbon atom selected from (1-4C)alkyl, halo, cyano, nitro, amino, (2-4C)alkanoylamino, (1-4C)alkoxy, hydroxy, oxo and thioxo (xe2x95x90S), and optionally substituted by a substituent on an available nitrogen atom selected from (1-4C)alkyl and oxo; and pharmaceutically-acceptable salts thereof.
Of the compounds in the above particular aspect, those in which the Het. moiety is a monocyclic ring are preferred.
An especially preferred compound of the invention is selected from the group consisting of:
N-[(5S)-3-(3-Fluoro-4-(4-pyrimidin-2-ylthiomethylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;
N-[(5S)-3-(3-Fluoro-4-(4-(2-furoyloxymethyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-yl-methyl]acetamide;
N-[(5S)-3-(3-Fluoro-4-(4-(5-nitropyridin-2-ylaminomethyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;
N-[(5S)-3-(3-Fluoro-4-(4-(quinoxalin-2-ylcarbonylaminomethyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;
N-[(5S)-3-(3-Fluoro-4-(4-(thiazol-2-ylaminocarbonyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide; and pharmnaceutically-acceptable salts thereof.
Of the above, N-[(5S)-3-(3-Fluoro-4-(4-(thiazol-2-ylaminocarbonyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide is especially preferred.
A further especially preferred compound of the invention is N-[(5S)-3-(3-Fluoro-4-(thiazol-2-ylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-yl-methyl]acetamide; and pharmaceutically-acceptable salts thereof.
In a further aspect the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The compounds of the formula (I) may be prepared by deprotecting a compound of the formula (II): 
wherein R2, R3, R5 and R6 are as hereinabove defined, R9 is R4 or protected R4 and R10 is R1 or protected R1, and thereafter if necessary forming a pharmaceutically acceptable salt.
Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in which xe2x80x9clowerxe2x80x9d signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
A carboxy protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
Examples of carboxy protecting groups include straight or branched chain (1-12C)alkyl groups (eg isopropyl, t-butyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); and (2-6C)alkenyl groups (eg allyl and vinylethyl).
Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, metal- or enzymically-catalysed hydrolysis.
Examples of hydroxy protecting groups include lower alkenyl groups (eg allyl); lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups (eg t-butoxycarbonyl); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, pmethoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, pnitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (eg trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl); aryl lower alkyl groups (eg benzyl) groups; and triaryl lower alkyl groups (eg triphenylmethyl).
Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, metal- or enzymically-catalysed hydrolysis, for groups such as o-nitrobenzyloxycarbonyl, photolytically and for groups such as silyl groups, fluoride.
Examples of protecting groups for amide groups include aralkoxymethyl (eg. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (eg. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (eg. trimethylsilyl, t-butyldimethylsily, t-butyldiphenylsilyl); tri alkyl/arylsilyloxymethyl (eg. t-butyldimethylsilyloxymethyl, t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (eg. 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (eg. 2,4-dimethoxyphenyl); 4-alkoxybenzyl (eg. 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (eg. 2,4-di(methoxy)benzyl); and alk-1-enyl (eg. allyl, but-1-enyl and substituted vinyl eg. 2-phenylvinyl).
Aralkoxymethyl, groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation. Alkoxymethyl, tri alkyl/arylsilyl and tri alkyl/silyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid, or in the case of the silyl containing groups fluoride ions. The alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with ceric ammonium nitrate. Finally alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid.
For further examples of protecting groups see one of the many general texts on the subject, for example, xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by Theodora Green (publisher: John Wiley and Sons).
In another aspect of the present invention the compounds of the formulae (I) and (II) and pharmaceutically acceptable salts thereof can be prepared:
(a) by modifying a substituent in or introducing a substituent into another compound of the formula (I) or (II), or modifying a linking group in another compound of the formula (I) or (II);
(b) by reaction of a compound of the formula (III) with a compound of the formula Hetxe2x80x94Yxe2x80x94L1 [wherein L1 and L2 are independently hydrogen or a leaving group], or with a compound capable of forming a Het. moiety [wherein L2 may form part of the final Het. moiety], or with a Hetxe2x80x94Yxe2x80x94L1 compound such that xe2x80x94Yxe2x80x94L1 or L2xe2x80x94Xxe2x80x94 (or a part thereof) may form part of the final xe2x80x94Xxe2x80x94Yxe2x80x94 link: 
(c) when R1 or R10 is of the formula xe2x80x94NHC(xe2x95x90O)Ra, by introducing xe2x80x94C(xe2x95x90O)Ra into a compound of the formula (I) or (II) wherein R1 or R10 is amino;
(d) when R1 or R10 is amino, by reducing a compound of the formula (I) or (II) wherein R1 or R10 is azido;
(e) when R1 or R10 is azido, by reacting a compound of the formula (IV) [wherein R12 is mesyloxy, tosyloxy or a phosphate ester] with a source of azide: 
(f) when R1 or R10 is hydroxy, by reacting a compound of the formula (V) with a compound of the formula (VI) [wherein R13 is (1-6C)alkyl or benzyl, and R14 is (1-5 6C)alkyl]: 
(g) when R10 is of the formula xe2x80x94N(CO2R15)CO(1-4C)alkyl [wherein R15 is (1-4C)alkyl or benzyl], from a compound of the formula (I) or (II) wherein R1 or R10 is hydroxy;
(h) when R5 or R10 is chloro, fluoro, (1-4C)alkanesulfonyloxy or (1-4C)alkylaminocarbonyloxy, from a compound of the formula (I) or (II) wherein R1 or R10is hydroxy;
(i) when R1 or R10 is chloro, (1-4C)alkylthio or (1-4C)alkoxy, from a compound of the formula (IV);
wherein L2, L1, X, Y, R2, R3, R5, R6 and R9 are as hereinabove or hereinafter defined, and thereafter if necessary:
i) removing any protecting groups;
ii) forming a pharmaceutically acceptable salt,
iii) forming a suitable N-oxide.
The processes (a) and (c) to (i) may be performed using compounds of the formula (I) or (II) as defined hereinbefore with compounds of the formula (II) in which R9 is xe2x80x94Xxe2x80x94L2 (or a protected version thereofxe2x80x94see hereinbefore and Examples for suitable protecting groups). The process (b) may then be performed using the compound in which xe2x80x94Xxe2x80x94L2 is unprotected. Certain values of assembled xe2x80x94Xxe2x80x94Yxe2x80x94 links in compounds of formula (I) and (II) (wherein R9 is R4 or protected R4) are unsuitable for use with processes (a) and (c) to (i); the skilled organic chemist will recognise when this is so, and, for example, the oxazolidinone ring should be assembled before the xe2x80x94Xxe2x80x94Yxe2x80x94 link is assembled.
Certain intermediate compounds described hereinbefore and hereinafter, for example those in which xe2x80x94Xxe2x80x94L2 in a compound of formula (II) is azidomethyl are novel and are provided as a further feature of the invention.
Process (a)
Methods for converting substituents into other substituents are known in the art. For example a cyano group reduced to an amino group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, a bromo group to a cyano group, a thio group oxidised to a sulfinyl or sulfonyl group, a (1-4C)alkoxycarbonyl group converted to a carbamoyl group (see Example 27, for example) or an amino group converted to a (2-4C)alkanoylamino group (see Example 48, for example).
A linking group in one compound of the formula (I) or (II) may be converted into another linking group, for example, a xe2x80x94COxe2x80x94 link may be converted into a xe2x80x94CH(OH) link.
Process (b)
It will be appreciated that process (b) provides means for assembling the xe2x80x94Xxe2x80x94Yxe2x80x94 link in compounds of the formula (I). In describing the reactions suitable for this assembly the terms L2xe2x80x94Xxe2x80x94 and xe2x80x94Yxe2x80x94L1 have been used to define certain intermediate compounds, but the terms L2, X, Y and L1 are not necessarily strictly limited to those defined hereinbefore. Thus, for example, amide links may be established by reaction of a compound of formula (III) in which L2xe2x80x94Xxe2x80x94 is a carboxy group (i.e. L2 is xe2x80x94OH and X is xe2x80x94COxe2x80x94) with a Het.xe2x80x94Yxe2x80x94L1 compound wherein Y is xe2x80x94NHxe2x80x94 and L1 is H. The xe2x80x94Xxe2x80x94Yxe2x80x94 link in this case (xe2x80x94CONHxe2x80x94) is provided for in the definition of compounds of formula (I) hereinbefore by X as a direct bond and Y as xe2x80x94CONHxe2x80x94 (CH2)mxe2x80x94 with m is 0. Thus, process (b) includes those processes in which compounds of formula (III) and Het.xe2x80x94Yxe2x80x94L1 are such that L2xe2x80x94Xxe2x80x94 and xe2x80x94Yxe2x80x94L1 (or a part thereof) are suitable to give an assembled xe2x80x94Xxe2x80x94Yxe2x80x94 link as defined hereinbefore. The skilled organic chemist will recognise from the range of assembled xe2x80x94Xxe2x80x94Yxe2x80x94 links and the description for process (b) given hereinbefore and hereinafter how such xe2x80x94Xxe2x80x94Yxe2x80x94 links may be assembled.
The coupling reaction between a compound of the formula (III) and a compound of the formula Hetxe2x80x94Yxe2x80x94L1 is conveniently performed in an inert solvent such as acetonitrile, dichloromethane, N,N-dimethylformamide or N,N-dimethylacetamide, at a temperature in the range 0xc2x0 C. to the reflux temperature of the solvent, preferably in the range ambient to 70xc2x0 C. The precise reaction conditions and the nature of the starting materials will depend upon the nature of the xe2x80x94Xxe2x80x94Yxe2x80x94 bond that is to be formed between the imidazole ring in the compound of formula (III) and the Het. group in R4 or R9. The skilled organic chemist will be able to select suitable starting materials and conditions to produce the range of xe2x80x94Xxe2x80x94Yxe2x80x94 bonds detailed in this specification, and non-limiting representative examples are provided in the Examples contained herein. Suitable values for the leaving groups L1 and L2 are provided below. For example:
Methylthio linkages (X is xe2x80x94CH2xe2x80x94, Y is xe2x80x94Sxe2x80x94) may be prepared by the reaction of an (activated) methylhydroxy compound (X is xe2x80x94CH2xe2x80x94, L2 is xe2x80x94OH or another suitable leaving group prepared from xe2x80x94OH) with a thioxo or thiol compound (xe2x80x94Yxe2x80x94L1 is =S, or Y is xe2x80x94Sxe2x80x94and L1 is xe2x80x94H) in the presence of an agent such as N,N-dimethylformarnmide dineopentylacetal (DMFDMPA) which activates the xe2x80x94OH group for displacement and also generates an in-situ base for generating the required nucleophile.
Methylamino linkages (X is xe2x80x94CH2NHxe2x80x94, Y is a direct bond) may be prepared by the reaction of a methylamino compound (X is xe2x80x94CH2NHxe2x80x94, L2 is xe2x80x94H) with, for example, a halo compound (xe2x80x94Yxe2x80x94L1 isxe2x80x94halo, Y is a direct bond, L1 is halo).
Amide (for example methylaminocarbonyl) linkages (X is xe2x80x94CH2NHxe2x80x94, Y is xe2x80x94COxe2x80x94) may be prepared by the reaction of a methylamino compound (X is xe2x80x94CH2NHxe2x80x94, L2 is xe2x80x94H) with an acid chloride compound (xe2x80x94Yxe2x80x94L1 is xe2x80x94COCl, Y is xe2x80x94COxe2x80x94, L1 is chloro). Other amide linkages (for example carbonylamino(1-4C)alkyl and carbonylamino; X is xe2x80x94CONHxe2x80x94, Y is xe2x80x94(CH2)nxe2x80x94 wherein n is 0, 1, 2 or 3) may be prepared by the reaction of an activated carboxy compound (Xxe2x80x94L2 is xe2x80x94CO2H, L2 is xe2x80x94OH) with an amine (xe2x80x94Yxe2x80x94L1 is xe2x80x94(CH2)nNH2, L1 is xe2x80x94H), optionally in the presence of a coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide. Suitable activated carboxy compounds are, for example, the esters formed from the reaction of the carboxy compound with 4-nitrophenol, or 1-hydroxybenzotriazole.
Amide linkages in which the nitrogen atom of the amide bond is provided by a ring nitrogen atom in a non-aromatic Het. moiety can be prepared from a carboxy compound (X is xe2x80x94COxe2x80x94, Y is xe2x80x94(CH2)nxe2x80x94 wherein n is 0, ie. a direct bond) may be prepared by the reaction of an activated carboxy compound (Xxe2x80x94L2 is xe2x80x94CO2H, L2 is xe2x80x94OH) with a non-aromatic nitrogen containing Het. compound (optionally with functionalities protected, xe2x80x94Yxe2x80x94 is a direct bond, xe2x80x94L1 is xe2x80x94H), optionally in the presence of a coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide.
Amide (urea or thiourea) linkages in which xe2x80x94Yxe2x80x94L1 or L2xe2x80x94Xxe2x80x94 may form part of the final xe2x80x94Xxe2x80x94Yxe2x80x94 link may be prepared from the reaction of a compound of the formula (III) in which L2xe2x80x94Xxe2x80x94 is an isocyanate or isothiocyanate group with a Het.xe2x80x94(CH2)m-amine (wherein m is 0 to 3). Alternatively, Het.xe2x80x94(CH2)mxe2x80x94NCO or Het.xe2x80x94(CH2)mxe2x80x94NCS may be reacted with a compound of the formula (III) in which L2xe2x80x94Xxe2x80x94 is an amine group (wherein m is 0 to 3). These reactions illustrate cases in which xe2x80x94Yxe2x80x94L1 or L2xe2x80x94Xxe2x80x94 is xe2x80x94(CH2)m-amine, or xe2x80x94(CH2)mxe2x80x94NCO or xe2x80x94(CH2)mxe2x80x94NCS.
Similarly, sulfonamide (for example methylaminosulfonyl) linkages (X is xe2x80x94CH2NHxe2x80x94, Y is xe2x80x94SO2xe2x80x94) may be prepared by the reaction of a methylamino compound (X is xe2x80x94CH2NHxe2x80x94, L2 is xe2x80x94H) with a sulfonyl chloride compound (xe2x80x94Yxe2x80x94L1 is xe2x80x94SO2Cl, Y is xe2x80x94SO2xe2x80x94, L1 is chloro).
Ester linkages (for example methoxycarbonyl) linkages (X is xe2x80x94CH2Oxe2x80x94, Y is xe2x80x94COxe2x80x94) may be prepared by the reaction of a methylhydroxy compound (X is xe2x80x94CH2Oxe2x80x94, L2 is xe2x80x94H) with carboxy compound (xe2x80x94Yxe2x80x94L1 is xe2x80x94CO2H, L1 is xe2x80x94OH) in the presence of a coupling agent such as DMFDMPA which activates the xe2x80x94OH group for displacement and also generates an in-situ base for generating the required nucleophile. Other ester linkages (for example carbonyloxymethyl; X is a direct bond, Y is xe2x80x94C(xe2x95x90O)Oxe2x80x94CH2xe2x80x94) may be prepared by the reaction of a carboxy compound (Xxe2x80x94L2 is xe2x80x94CO2Hxe2x80x94, L2 is xe2x80x94OH) with a methylhydroxy compound (xe2x80x94Yxe2x80x94L1 is xe2x80x94CH2OH, L1 is xe2x80x94H) in the presence of a coupling agent such as dimethylarninopyridine and dicyclohexylcarbodiimide.
Alkylene chain linkages (for example X is methylene, xe2x80x94CH2xe2x80x94) to a ring nitrogen atom in a non-aromatic Het. moiety can be prepared, for example, by reaction of a methylhydroxy compound (X is xe2x80x94CH2xe2x80x94, L2 is xe2x80x94OH) with a non-aromatic Het. compound (optionally with functionalities protected, xe2x80x94Yxe2x80x94 is a direct bond, xe2x80x94L1 is xe2x80x94H), optionally in the presence of a coupling agent such as N,N-dimethylformamide dineopentylacetal (DMFDMPA) which activates the xe2x80x94OH group for displacement and also generates an in-situ base for generating the required nucleophile.
Direct bond linkages (in which the Het. moiety of R4 is linked directly to the imidazole ring in the compound of formula (III)) may be formed, for example by reaction of a compound of formula (III) in which L2xe2x80x94Xxe2x80x94 is formyl (L2 is xe2x95x90O here) with a compound capable of forming a Het. moiety incorporating the formyl carbon atom as part of the Het. ring. Thus, as illustrated in Examples 81 and 82, a diamine (such as 2-aminoaniline) may be reacted with the formyl compound (to give a benzimidazole moiety as Het., directly C-linked to the imidazole ring of the product compound).
The reaction between a compound of the formula (III) and a compound capable of forming a Het. moiety may be performed, for example, using a compound of the formula (III) in which L2xe2x80x94Xxe2x80x94 is azidomethyl to form a 1,2,3-triazole ring upon reaction with ethyl propiolate. In this case L2 is not a leaving group as all three nitrogen atoms of the azido group are incorporated in the 1,2,3-triazole ring.
Compounds of the formula (III) may be prepared by using the processes described in this specification, and as, for example, illustrated in the accompanying Examples. Thus, for example, a compound of the formula (III) in which L2xe2x80x94Xxe2x80x94 is hydroxymethyl may be prepared using process (f), ie. from a compound of the formula (V) in which R9 is hydroxymethyl (or protected hydroxymethyl). This hydroxymethyl group may be modified to a azidomethyl group, which may then be reduced to an aminomethyl group (see, for example, Example 19 preparation of intermediate). Such modifications are known in the art. The hydroxymethyl group may also be oxidised to an alkanoyl (eg. formyl) group, and further oxidised to a carboxy group, using known oxidising techniques and reagents.
The preparation of compounds of the formula Het.xe2x80x94Yxe2x80x94L1, Het.xe2x80x94(CH2)m-amine, Het.xe2x80x94(CH2)mxe2x80x94NCO or Het.xe2x80x94(CH2)mxe2x80x94NCS (wherein m is 0 to 3) and of compounds capable of forming a Het. moiety, is within the skill of the skilled organic chemist, or are cornmercially available.
Process (c)
When Ra is (1-4C)alkyl, the group xe2x80x94C(xe2x95x90O)(1-4C)alkyl may be introduced into a compound of the formula (I) or (II) wherein R1 or R10 is amino by standard acetylation procedures. For example, the amino group may be acetylated to give an acetamido group using the Schotten-Baumann procedure i.e. reacting the compound of the formula (I) or (II) wherein R1 or R10 is amino with acetic anhydride in aqueous sodium hydroxide and THF in a temperature range of 0xc2x0 C. to 60xc2x0 C. , preferably between 0xc2x0 C. and ambient temperature. The acylation may be carried out in situ following the catalytic hydrogenation of a compound of the formula (I) or (II) wherein R1 or R10 is azido, by performing the hydrogenation in the presence of acetic anhydride (for example using similar methods to those used in example 4).
When Ra is hydrogen, the xe2x80x94CHO group may be introduced into the compound of the formula (I) or (II) wherein R1 or R10 is amino (amino compound) by reacting the latter compound in formic acetic anhydride, in an inert organic solvent such as THF, in a temperature range of 0xc2x0 C. to ambient temperature, or by reacting it with ethyl formate in an inert organic solvent in the temperature range of 50-100xc2x0 C.
When Ra is (1-4C)alkoxy, the xe2x80x94COO(1-4C)alkyl group may be introduced into the amino compound by reacting the latter compound with (1-4C)alkyl chloroformate, in the presence of an organic base such as triethylamine, in an organic solvent such as dichloromethane and in a temperature range of 0xc2x0 C. to ambient temperature.
When Ra is chloromethyl, dichloromethyl, cyanomethyl or methoxymethyl, the xe2x80x94C(xe2x95x90O)Ra group may be introduced into the amino compound by reacting the latter compound with the appropriate acid chloride under standard conditions. The acid chloride may be prepared from the appropriate acid. When Ra is acetyimethyl, the xe2x80x94C(xe2x95x90O)Ra group may be introduced into the amino compound by reacting the latter compound with diketene, in an inert organic solvent such as THF, in a temperature range of 0xc2x0 C. to ambient temperature.
Alternatively, the amino compound may be reacted with the appropriate acid anhydride, in dichloromethane or THF, in the presence of an organic base such as triethylamine and in a temperature range of 0xc2x0 C. to ambient temperature, or the amino compound may be reacted with the appropriate acid in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic base such as triethylamine, in an organic solvent such as dichloromethane, in a temperature range of 0xc2x0 C. to ambient temperature.
Process (d)
Suitable reducing agents for reducing azido to amino in a compound of the formula (I) or (II) include triethylamine/hydrogen sulfide, triphenylphosphine or phosphate ester, or hydrogen in the presence of a catalyst. More specifically the reduction of the azido group may be carried out by heating it in an aprotic solvent, such as 1,2-dimethoxyethane, in the presence of P(OMe)3 and subsequently heating in 6N aqueous hydrochloric acid, or reacting it with hydrogen in the presence of palladium on carbon in a protic such as DMF or ethyl acetate. For further details on the reduction of azides to amines see U.S. Pat. No. 4,705,799. The azido compound may be reduced and converted to a compound of the formula (I) or (II), wherein R1 or R10 is acetamido, in situ using acetic anhydride in DMF.
Process (e)
A compound of the formula (I) or (II) wherein R1 or R10 is azido may be prepared, for example, by reacting a compound of the formula (IV) with sodium azide in an inert solvent such as DMF in a temperature range of ambient to 100xc2x0 C., normally in the region of 75xc2x0 C.-85xc2x0 C., A compound of the formula (IV) may be prepared by converting the hydroxy group in a compound of the formula (I) or (II) wherein R1 or R10 is hydroxy into a tosyloxy or mesyloxy group by standard methods known in the art. For example, by reacting a compound of the formula (I) or (II) wherein R1 or R10 is hydroxy with tosyl chloride, mesyl chloride or a chlorophosphate ester in the presence of a mild base such as triethylamine, or pyridine.
Process (f)
Compounds of the formulae (V) and (VI) are conveniently reacted together in the presence of a strong base such as butyl lithium, lithium bistrimethylsilylamide, sodium hydride, or lithium diisopropylamnide. The reaction is conveniently carried out in an inert solvent such as tetrahydrofuran (THF), dimethylformamide (DMF), N,N1-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone in a temperature range of xe2x88x9278xc2x0 C. to xe2x88x9250xc2x0 C. for the deprotonation and cyclisation. Suitable values for R13 include ethyl and benzyl and suitable values for R14 include ethyl and n-propyl, preferably n-propyl.
A compound of the formula (V) is conveniently prepared by reacting a chloroformate of the formula (ClCOOR13) with a compound of the formula (VA): 
wherein R2, R3, R5, R6 and R9 are as hereinabove defined. The reaction is conveniently carried out in the presence of an inorganic or organic base such as sodium bicarbonate or an amine base such as dimethylaniline, the former in a solvent such as acetone/water and the latter in an organic solvent such as TRF, toluene, DMF or acetonitrile.
A compound of the formula (VA) may be prepared by reducing a compound of the formula (VB): 
wherein R2, R3, R5, R6 and R9 are as hereinabove defined.
Many reduction methods suitable for the reduction of a nitro to an amino group are known in the art, for example catalytic hydrogenation, metal reductions or with reducing agents such as sodium hydrosulfite. Suitable catalysts in catalytic hydrogenation include Raney nickel, platinum metal and its oxide, rhodium, palladium-on-charcoal and Wilkinson""s catalyst RhCl (Ph3P)3. Catalyst hydrogenation is conveniently carried out in the temperature range 0xc2x0 C.-50xc2x0 C., but preferably at ambient temperature at slightly above atmospheric pressure.
A compound of the formula (VB) is conveniently prepared by reacting together compounds of the formulae (VC) and (VD): 
wherein R2, R3, R5, R6 and R9 are as hereinabove defined and L3 is a leaving group, preferably halo and in particular fluoro.
The reaction between compounds of the formulae (VC) and (VD) is carried out in the presence of an organic or inorganic base such as sodium bicarbonate, potassium carbonate or an amine base such as diisopropylethylamine, in an inert solvent such as acetonitrile, DMF, DMPU or N-methylpyrrolidone, in a temperature range of 50xc2x0 C.-150xc2x0 C.
Compounds of the formula (VC) may be prepared by introducing substituents into or modifying substituents in a known optionally substituted imidazole ring. Such conversions are well known to the skilled chemist, for example a cyano group may be hydrolysed to a carboxy group which in turn may be converted to a carbamoyl or alkoxycarbonyl group or reduced to a hydroxymethyl group; an amino group may be acylated to an alkanoylamino group; a thio group may be alkylated to an alkylthio group which in turn may be oxidised to an alkylsulfinyl or alkylsulfonyl group and a hydroxyalkyl group may be alkylated to an alkoxyalkyl group.
Alternatively compounds of the formula (VC) may be prepared using the methods described in Houben-Weyl, Methoden der organischen Chemie, Heterarene III Teil 3, ed E Schaumann (1994), or The Chemistry of Heterocyclic Compounds, Vol 6, Part 1 xe2x80x9cImidazole and its Derivativesxe2x80x9d (1953).
Process (g)
A compound of the formula (II) wherein R10 is of the formula xe2x80x94N(CO2R15)CO(1-4C)alkyl is conveniently prepared by reacting a compound of the formula (I) and (II) wherein R1 or R10 is hydroxy with an amide of the formula HN(CO2R15)CO(1-4C)alkyl under Mitsunobu conditions. For example, in the presence of tri-n-butylphosphine and 1,1xe2x80x2-(azodicarbonyl)dipiperndine in an organic solvent such as THF, and in the temperature range 0xc2x0 C.-60xc2x0 C., but preferably at ambient temperature. Details of analogous Mitsunobu reactions are contained in Tsunoda et al., Tet. Letts., 34, 1639, (1993). Amides of the formula HN(CO2R15)CO(1-4C)alkyl may be prepared by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist.
Process (h)
A compound of the formula (I) or (II) wherein R1 or R10 is fluoro may be prepared by reacting a compound of the formula (I) or (II) wherein R1 or R10 is hydroxy (hydroxy compound) with a fluorinating agent such as diethylaminosulfur trifluoride in an organic solvent such as dichloromethane in the temperature range of 0xc2x0 C. to ambient temperature.
When R1 or R10 is chloro, the compound of the formula (I) or (II) may be formed by reacting the hydroxy compound with a chlorinating agent. For example, by reacting the hydroxy compound with sulfinyl chloride in a temperature range of ambient temperature to reflux, optionally in a chlorinated solvent such as dichloromethane or by reacting the hydroxy compound with carbon tetrachloride/triphenyl phosphine in dichloromethane, in a temperature range of 0xc2x0 C. to ambient temperature.
The (1-4C)alkanesulfonyloxy compound may be prepared by reacting the hydroxy compound with (1-4C)alkanesulfonyl chloride in the presence of a mild base such as triethylamine or pyridine.
The (1-4C)alkylaminocarbonyloxy compound may be prepared by reacting the hydroxy compound with (1-4C)alkyl cyanate in an organic solvent such as THF or acetonitrile, in the presence of triethylamine, in a temperature range of 0xc2x0 C. to 50xc2x0 C.
Process (i)
A compound of the formula (I) or (II) wherein R1 or R10 is chloro may also be prepared from a compound of the formula (IV), by reacting the latter compound with lithium chloride and crown ether, in a suitable organic solvent such as THF, in a temperature range of ambient temperature to reflux. A compound of the formula (I) or (II) wherein R1 or R10 is (1-4C)alkylthio or (1-4C)alkoxy may be prepared by reacting the compound of the formula (IV) with sodium thio(1-4C)alkoxide or sodium (1-4C)alkoxide respectively, in an alcohol or THF, in a temperature range of 0xc2x0 C. to reflux.
Suitable N-oxides of compounds of the formula (I) or (II) may be prepared directly from a corresponding parent compound of the formula (I) or (II) using techniques well known to the ordinary skilled organic chemist, such as, for example, using a peracid (such as m-chloroperbenzoic acid) or perphthalic acid in a suitable solvent (such as dioxan or a mixture of water and THF) at a suitable temperature (such as ambient temperature). The preparation of suitable N-oxides by assembly from suitable N-oxide starting materials and the use of the processes described in this specification is within the skill of the ordinary skilled organic chemist, and is illustrated by, for example, Example 5.
When an optically active form of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using an optically active starting material or by resolution of a racemic form of the compound or intermediate using a standard procedure.
According to a further feature of the invention there is provided a compound of the formula (I), or a pharmnaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy,
According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt thereof.
The invention also provides the use of a compound of the present invention, or a pharmaceutically-acceptable salt thereof, for use as a medicament; and the use of a compound of the present invention, or a pharmaceutically-acceptable salt thereof, in the manufacture of a novel medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.
In order to use a compound of the formula (I) or a pharmaceutically-acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmnaceutically-acceptable salt thereof and a pharmaceutically-acceptable diluent or carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents (for example xcex2-lactams or aminoglycosides). These may include penicillins, for example oxacillin or flucloxacillin, carbapenems (for example meropenem or imipenem) and monobactams (for example aztreonam) to broaden the therapeutic effectiveness. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 5 mgkg-1 to 20 mgkg-1 of the compound of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
Antibacterial Activity
The pharmaceutically acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard Gram-positive organisms, which are used to screen for activity against pathogenic bacteria. Notably, the pharmaceutically acceptable compounds of the present invention show activity against enterococci, pneumococci and methicillin resistant strains of S. aureus and coagulase negative staphylococci. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.
The antibacterial properties of the compounds of the invention may also be demonstrated in vivo in conventional tests.
The following results were obtained on a standard in vitro test system. The activity is described in terms of the minimum inhibitory concentration (MIC) determined by the agar-dilution technique with an inoculum size of 104 CFU/spot.
The organisms were tested on a standard semi-defined susceptability test medium (IsoSensitest agar), using an inoculum of 104 CFU/spot and an incubation temperature of 37xc2x0 C. for 24 hours.
Novb. Res=Novobiocin resistant
MRQR=methicillin resistant quinolone resistant
MR=methicillin resistant